This invention relates to transgenic animals.
Transgenic animals carry a gene which has been introduced into the germline of the animal, or an ancestor of the animal, at an early (usually one cell) developmental stage. Leder et al. U.S. Pat. No. 4,736,866, hereby incorporated by reference, describes transgenic animals whose germ and somatic cells contain an activated oncogene sequence introduced into the animal at an embryonic stage. Wagner et al. (1981) Proc. Nat. Aca. Sci. 78, 5016; and Stewart et al. (1982) Science 217, 1046 describe transgenic mice containing human globin genes. Constantini et al. (1981) Nature 294, 92; and Lacy et al. (1983) Cell 34, 343 describe transgenic mice containing rabbit globin genes. McKnight et al. (1983) Cell 34, 335 describes transgenic mice containing the chicken transferring gene. Brinster et al. (1983) Nature 306, 332 describes transgenic mice containing a functionally rearranged immunoglobulin gene. Palmiter et al. (1982) Nature 300, 611 describes transgenic mice containing the rat growth hormone gene fused to a heavy metal-inducible metallothionein promoter sequence. Palmiter et al. (1982) Cell 29, 701 describes transgenic mice containing a thymidine kinase gene fused to a metalothionein promoter sequence. Palmiter et al. (1983) Science 222, 809 describes transgenic mice containing the human growth hormone gene fused to a metallothionein promoter sequence.
The existence of potential oncogenes in the DNA of normal somatic cells has been demonstrated by Weinberg, 1981, Biochem. Biophys. Acta 651:25-35 and Bishop et al., 1982, The Molecular Biology of Tumor Viruses, Part III, RNA Tumor Viruses, Chp. 9, Weiss et al., eds., Cold Spring Harbor, N.Y., Cold Spring Harbor Laboratory. Neoplasia is believed to result at least in part from abnormal expression of an endogenous gene, either at abnormally high levels or in some altered or mutated form (Hayward et al., 1981, Nature 290:475-480; Payne et al., 1982, Nature 295:209-214; Reddy et al., 1982, Nature 300:149.varies.152; Tabin et al., 1982, Nature 300:143-149; Taparowski et al., 1982, Nature 300:762-765). Nusse et al., 1982, Cell 31:99-109 and Peters et al., 1982, J. Virol. 42:880-888 identified two cellular loci, int-1 and int-2, which harbor an MMTV provirus in a majority of virally induced mammary tumors. These loci share no apparent homology with known cellular or viral oncogenes. Dickson et al., 1984, Cell 37:529-536 showed that more than 50% of the mammary tumors arising in BR6 mice contain an acquired MMTV provirus integrated within a defined 25 kb domain of DNA on mouse chromosome 7. Moore et al., 1986, EMBO J. 5:919-924 characterized the int-2 region and isolated a cDNA clone which contains the int-2 gene and which may encode a protein of approximately 27 kD.
There is demonstrable homology between the int-2 gene and members of the family of fibroblast growth factor (FGF) related oncogenes. Basic and acidic FGF have been implicated in endothelial cell proliferation and migration during angiogenesis, in mesodermal induction in Xenopus (Gospodarowicz, 1986, Mol. Cell. Endocrinol. 46:187-204; Folkman and Klagsbrun, 1987, Science 235:442-447; Slack et al., 1987, Nature 326:197-200), and in the formation of nonmammary human tumors (Delli Bovi et al., 1987, Cell 50:729-737 and Taira et al., 1987, Proc. Nat. Aca. Sci. 84:2980-2984).